Abstract

Despite the success of potent anti-retroviral drugs in controlling human immunodeficiency virus type 1 (HIV-1) infection, little progress has been made in generating an effective HIV-1 vaccine. Although passive transfer of anti-HIV-1 broadly neutralizing antibodies can protect mice or macaques against a single high-dose challenge with HIV or simian/human (SIV/HIV) chimaeric viruses (SHIVs) respectively1,2,3,4,5,6,7,8, the long-term efficacy of a passive antibody transfer approach for HIV-1 has not been examined. Here we show, on the basis of the relatively long-term protection conferred by hepatitis A immune globulin, the efficacy of a single injection (20 mg kg−1) of four anti-HIV-1-neutralizing monoclonal antibodies (VRC01, VRC01-LS, 3BNC117, and 10-1074 (refs 9, 10, 11, 12)) in blocking repeated weekly low-dose virus challenges of the clade B SHIVAD8. Compared with control animals, which required two to six challenges (median = 3) for infection, a single broadly neutralizing antibody infusion prevented virus acquisition for up to 23 weekly challenges. This effect depended on antibody potency and half-life. The highest levels of plasma-neutralizing activity and, correspondingly, the longest protection were found in monkeys administered the more potent antibodies 3BNC117 and 10-1074 (median = 13 and 12.5 weeks, respectively). VRC01, which showed lower plasma-neutralizing activity, protected for a shorter time (median = 8 weeks). The introduction of a mutation that extends antibody half-life into the crystallizable fragment (Fc) domain of VRC01 increased median protection from 8 to 14.5 weeks. If administered to populations at high risk of HIV-1 transmission, such an immunoprophylaxis regimen could have a major impact on virus transmission.

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Acknowledgements

We thank R. Plishka, A. Peach, and T. Lewis for determining plasma viral RNA loads, and K. Rice, R. Engel, R. Petros, and S. Fong for assisting in the maintenance of animals and assisting with procedures. We also thank R. Schwartz for clinical-grade VRC01 and VRC01-LS, and X. Chen for protein reagents for ELISA. We thank the National Institutes of Health (NIH) AIDS Research and Reference Reagent Program for TZM-bl cells. We thank R. Fast for ultrasensitive plasma SIV RNA assays and W. Bosche and M Hull for ultrasensitive peripheral blood mononuclear cell SIV RNA/DNA assays. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH and, in part, with federal funds from the National Cancer Institute, NIH, under contract number HHSN261200800001E (to J.D.L.). The research was also funded in part by the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery Grants OPP1033115 and OPP1092074 (to M.C.Nu.), by the NIH under award numbers AI-100148, UM1 AI100663-01. M.C.Nu. is supported by the Robertson Foundation and the The Howard Hughes Medical Institute.

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Author notes

    • Rajeev Gautam
    •  & Yoshiaki Nishimura

    These authors contributed equally to this work.

Affiliations

  1. Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA

    • Rajeev Gautam
    • , Yoshiaki Nishimura
    • , Alicia Buckler-White
    • , Reza Sadjadpour
    •  & Malcolm A. Martin
  2. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA

    • Amarendra Pegu
    • , Keyun Wang
    • , Zachary Mankoff
    • , Stephen D. Schmidt
    •  & John R. Mascola
  3. Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA

    • Martha C. Nason
  4. Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA

    • Florian Klein
    • , Anna Gazumyan
    • , Jovana Golijanin
    •  & Michel C. Nussenzweig
  5. Laboratory of Experimental Immunology, Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany

    • Florian Klein
  6. Department I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, 50937 Cologne, Germany

    • Florian Klein
  7. AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA

    • Jeffrey D. Lifson
  8. Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA

    • Michel C. Nussenzweig

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Contributions

R.G., Y.N., M.A.M., M.C.Nu., and J.R.M. designed experiments; R.G., Y.N., A.P., F.K., A.G., J.G., A.B.W., R.S., K.W., Z.M., and S.D.S. performed experiments; R.G., Y.N., M.C.Na., M.A.M., M.C.Nu., J.R.M., and J.D.L. analysed data; R.G., Y.N., M.A.M., M.C.Nu., J.R.M., and J.D.L. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Malcolm A. Martin.

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https://doi.org/10.1038/nature17677

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